Description of interventions & intervention delivery

Illustrative example - WHO pre-eclampsia trial

‘The women will be randomized to receive either a calcium supplement or a placebo from the time of enrolment, until delivery or initiation of any magnesium sulphate treatment, or the suspicion of urolithiasis. Women starting antenatal care before the twentieth week will be randomized at the first visit. Most of the women will therefore be supplemented for approximately five to six months. The diagnosis of pre-eclampsia or hypertension is not a reason for discontinuation of treatment.

There will be three chewable tablets containing 500 mg elemental calcium to be taken every day. Women will be instructed to chew tablets at meals, but at least 3 hours away from any iron supplements. The control group will receive three tablets a day of identical characteristics, colour and taste as the intervention tablet prepared and packed by the same pharmaceutical manufacturer. All women will be encouraged not to take any additional calcium supplements. For those women who need analgesics, acetaminophen, and for those needing antacids, a non-calcium antacid will be recommended.’ (WHO Multicentre Randomized Trial of Calcium Supplementation for the Prevention of Pre-eclampsia - go to protocol)

Illustrative example - Magpie trial

As soon as a woman has been allocated a treatment pack, the pack is opened and the trial treatment inside given as directed.  Each treatment pack contains 9 x 10ml ampoules of either 50% magnesium sulphate (5g per ampoule;1g/2ml) or placebo, 1g ampoule of calcium gluconate (10ml) in case of toxicity, and an Eclampsia Rescue Pack.  Participating hospitals choose whether to use the intravenous or the intramuscular route for maintenance therapy.  All other aspects of care are at the discretion of the attending clinician. 

The safe use of magnesium sulphate relies on careful monitoring of tendon reflexes, respiratory rate and urine output.  Before the trial treatment is started, the clinician checks:

• knee or other tendon reflexes are present

• respiratory rate is normal (>16 respirations/minute)

• urine output was >100ml over the last 4 hours, or >25ml/hour

If tendon reflexes are slow, respiratory rate is reduced but the woman is well oxygenated, or urine output is <25ml/hour treatment can be started, but with half the stated volume of trial treatment for each dose.

If using the INTRAVENOUS route for maintenance therapy:

• To give the loading dose take 8ml from ampoule 1, dilute with normal saline as usual, and give IV over 10-15 minutes.

• To give maintenance therapy Take 10ml from ampoule 2, dilute with normal saline as usual, and give as an IV infusion equivalent to 2ml trial treatment/hour.  Continue for 24 hours using ampoules 3-6. Ampoules 7-9 are extra, use if needed.

If using the INTRAMUSCULAR route for maintenance therapy:

• To give the loading dose Take 8ml from ampoule 1, dilute with normal saline as usual and give IV over 10-15 minutes. Take 10ml from ampoule 2 and inject IM into one buttock, then take 10ml from ampoule 3 and inject into the other buttock.

• To give maintenance therapy Give 10ml IM into alternate buttocks every 4 hours, using ampoules 4-8. This is 24 hours‘ treatment, and means the last dose is given 20 hours after the loading dose. Ampoule 9 is extra, use if needed.

Subsequent care for all women entered into the trial should be based on the assumption that they were given magnesium sulphate. (MAGPIE Trial - go to protocol)

Illustrative example - CRASH trial

The study computer will then randomly assign a treatment pack number that will identify one of the CRASH treatment packs stored in the emergency department.

CRASH treatment pack contains:

• 11 x 2g vials of methylprednisolone (MP) or placebo 

• 1 x 20mL sterile water for injection (for use with the loading dose)

• 1 x 100mL bag of 0.9% NaCl (for use with the loading dose) 

• CRASH stickers (for attaching to infusion bags and patient notes)

• Patient information leaflet and Early Outcome Forms

Loading

2g MP (or matching placebo) over 1 hour in 100mL infusion:

1. Add 20mL water for injection to one 2g vial and mix well

2. Add contents of vial to the 100mL bag of 0.9% NaCl provided

3. Infuse over one hour

Daily Maintenance

0.4g/hour for about 24 hours in 20mL/hour infusion (MP or matching placebo):

1. Remove 100mL from a 500mL bag of 0.9% NaCl (to make room for the steroid)

2. Add 20mL water for injection to each of five 2g vials and mix well

3. Add all five (total 100mL) to the 500mL bag of 0.9% NaCl

4. Infuse at 20mL/hour for about 24 hours

5. Repeat for maintenance day 2

N.B. As children under 16 are excluded, a simple fixed-dose treatment can be used.  The dosing regimen is that used in the NASCIS-2 and NASCIS-3 trials of MP in acute spinal cord injury. (CRASH Trial - go to protocol)

Illustrative example - Cluster trial example: RaPP trial

The practical implementation of the intervention will be initiated through an educational outreach visit carried out by pharmacists recruited specifically for this purpose. The main elements of the guideline will be presented, with special emphasis on risk estimation, choice of first-line drugs, and treatment goals. A printed copy of the guideline and a one-page version will be given to the physicians, including a chart to aid the estimation of cardiovascular risk. 

During the visit a software package will be installed. This enables us to extract data and immediately, during the visit, present the physicians with data on their performance concerning risk estimation, choice of antihypertensive drugs and achievement of treatment goals (“audit and feed-back”). The software package also includes computerized reminders using ”pop-ups” on the computer screen. These are triggered at the patient’s first visit following a recording of an elevated blood pressure- or cholesterol-level (blood pressure >140/90 mm Hg or total-cholesterol > 5 mmol/L or LDL-cholesterol > 3mmol/L).

If the patient has not been prescribed blood-pressure- or cholesterol-lowering drugs the physician is reminded of the recommendation to carry out cardiovascular risk assessment and is offered to start a computerized risk assessment tool (SmartHeart). Recommendations on choice of drugs are also given and the physician is also given the option of printing out patient information material.

If the patient has been prescribed blood-pressure- or cholesterol-lowering drugs, the “pop-up” will remind the physician of recommended treatment goals and ask if the physician would like to print out patient information material. (RaPP Trial - go to protocol)